tbuckley/cabot-search huggingface dataset:
Abstract 5397: Gene signatures for predicting patients with aggressive type of bladder cancer and shorter survivals
Authors: Jim Jinn-Chyuan Sheu, Bo-Chen Lin, Oscar Yang, Chung Chang
Journal: Cancer Research (2022)

Abstract Bladder cancer is frequently associated with high recurrence and metastasis. With the success of cancer genome project in bladder cancer, we aimed to discover novel cancer drivers in muscle-invasive bladder cancer (MIBC), the most aggressive type of bladder cancer. A total of 155 genes were filtered out using RNAseq data from the TCGA cohort (n = 367), which are overexpressed (Z scores &amp;gt; 2.0) in more than 5% patients and correlated with poor overall survivals by Cox regression (p-value &amp;lt; 0.05) and FDR correction (q-value &amp;lt; 0.05). Using a unique HD-MAC (high-dimensional analysis of molecular alterations in cancer) algorithm developed by our team, 25 genes were further selected which show statistical significances as independent prognosis biomarkers for shorter overall survivals. Through clinical association study (including tumor stage, lymph node invasion, angiogenesis, and metastasis) by using CGDSR (Cancer Genomics Data Server in R), five most significant genes were further filtered which can be validated by another cohort (GSE13507). Although those genes show no direct gene-gene interactions, gene set enrichment analysis (GSEA) revealed common pathways governed by those driver genes, including cancer-related signaling, glycome alterations for TME remodeling, regulation in cell death, glutamate &amp; neuronal signaling, and ER-Golgi transportation. The above findings can be also confirmed at the protein levels by IHC staining. In this study, how those key genes assist cell survival under nutrition crisis and their impacts on aggressive behaviors of bladder cancer will be discussed. Citation Format: Jim Jinn-Chyuan Sheu, Bo-Chen Lin, Oscar Yang, Chung Chang. Gene signatures for predicting patients with aggressive type of bladder cancer and shorter survivals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5397.
Abstract 3882: Translating genotype to immunophenotype in HRAS mutated head and neck squamous cell carcinoma (HNSCC) to identify effective Tipifarnib partners for optimal patient outcomes
Authors: Amanda Psyrri, Miriam Anastasiou, Aris Spathis, Stergios Doumas, Panagiota Economopoulou, Ioannis Kotsantis, Anastasios Pantazopoulos, Anastasios Kyriazoglou, George Kavourakis, Theodoros Rampias, Periklis Foukas
Journal: Cancer Research (2022)

Abstract Background: Tipifarnib is a highly selective farnesyltransferase inhibitor that has shown promising activity in HRAS mutant recurrent/metastatic HNSCC. The incidence of HRAS mutations in HNSCC is 4-10%. Since HRAS mutated HNSCC can be successfully targeted with Tipifarnib, we sought to analyze the immune and genomic landscape of these tumors to guide combinatorial strategies. Methods: We identified thirteen patients with HRAS mutant tumors. We included in the analysis 50 patients with HRAS wild-type tumors. Genomic DNA from baseline biopsies of tumors was purified and subjected to targeted sequencing (TruSightTM Oncology 500 panel). PD-L1 expression in formalin-fixed tumor samples was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA) and characterized by the combined positive score (CPS). Assessment of PD-L1+ cells inside and at the periphery of the tumor was performed. HRAS mutational status was correlated with PD-L1 status. The genomic data derived from the targeted gene panel of HRAS mutant tumors were compared to those with wild-type HRAS. Results: Thirty-seven patients had both genomic and PD-L1 expression data available. The presence of HRAS mutations was associated with higher TPS PD-L1 scores (26% vs 40% vs 100% in TPS &amp;lt;1%, 1-49% and &amp;gt;50% respectively, p=0.043). Similar results were obtained for CPS (28% vs 80% in CPS &amp;lt;10% and =&amp;gt;10%, p=0.047). HRAS mutations were more commonly found with TP53 mutations (16% in WT TP53 and 55.6% in mutated TP53, p=0.073). Higher PD-L1 TPS showed increased survival without reaching significance when measuring either in the margins (64.1 vs 35.8, p=0.066) or the center of the tumor (p=0.097) due to the small sample size. Conclusions: HRAS mutant HNSCC are associated with high PD-L1 expression and co-occurrence of p53 mutations. Combinations of tipifarnib with an anti-PD1 antibody, an anti-PDL1 antibody, or an anti-CTLA-4 antibody warrant clinical investigation in this rare subset of HNSCC. Citation Format: Amanda Psyrri, Miriam Anastasiou, Aris Spathis, Stergios Doumas, Panagiota Economopoulou, Ioannis Kotsantis, Anastasios Pantazopoulos, Anastasios Kyriazoglou, George Kavourakis, Theodoros Rampias, Periklis Foukas. Translating genotype to immunophenotype in HRAS mutated head and neck squamous cell carcinoma (HNSCC) to identify effective Tipifarnib partners for optimal patient outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3882.
Abstract 763: Linking Down syndrome, clonal hematopoiesis, and autophagy
Authors: Edward James Evans, Ross Granrath, Keith Smith, Joaquin Espinosa, Andrew Thorburn, James DeGregori
Journal: Cancer Research (2022)

Abstract Down syndrome (DS) is the result of trisomy in chromosome 21 (T21) and is associated with an increased risk of diseases, particularly acute myeloid leukemia (AML). However, people with DS have variable disease risks and severities that have yet to be explained. We hypothesize that differing characteristics of clonal hematopoiesis (CH) may coincide with and/or contribute to poor health outcomes seen in people with DS and can help explain differences in disease outcome. To characterize CH, we use a rare-mutation detection technique called Duplex Seq, only requiring a blood draw to obtain the DNA from leukocytes. This targeted-sequencing tool uses a double-stranded tag to incorporate mutational data from both strands of DNA, enabling high sensitivity through the elimination of DNA processing errors. Using bioinformatics and COSMIC’s Cancer Gene Census, we have established differences in mutational patterns that enable us to distinguish people with DS from people without DS and characterize the variability among people with DS. Notably, protein-altering mutations in genes responsible for the differentiation of hematopoietic stem and progenitor cells are more prevalent among people with T21 than their counterparts who are disomic in chromosome 21 (D21). Coupling our genomic findings with other -omics approaches, we have drawn associations between the observed mutations and phenotypes of these individuals. Using mouse models of DS (Dp16, Dp17, and Dp10), we plan to investigate the susceptibility of CH and leukemogenesis with the use of a Moloney Murine Leukemia virus, expecting the mice modeling DS to have more prevalent CH and more leukemias. Furthermore, based on our analyses of leukocytic gene expression differences between people with DS with or without CH, we believe that people with DS have a varying reduction in autophagy that enables the presence of harmful CH and increased disease risk in some individuals. Using a GFP-LC3-RFP construct, we plan to quantify and compare basal autophagic flux between the mouse models of DS and their control littermates. This will enable us to draw the links between DS, CH, and autophagy. Future work will be centered around manipulating autophagy using transgenic mice and non-invasive interventions to see if deleterious phenotypes and risks to AML can be reversed. Overall, these studies offer a means by which disease risk in people with DS can be monitored through CH and a potential mechanism that can be altered by non-intrusive means to improve longevity and quality of life. Citation Format: Edward James Evans, Ross Granrath, Keith Smith, Joaquin Espinosa, Andrew Thorburn, James DeGregori. Linking Down syndrome, clonal hematopoiesis, and autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 763.
Abstract 772: Single cell whole genome sequencing to assess tumor heterogeneity in endometrial cancer
Authors: Enrique Velazquez Villarreal, Lee D. Gibbs, Dana Mahinbakht, Diane M. Da Silva, Lynda D. Roman, David W. Craig, John D. Carpten
Journal: Cancer Research (2022)

Abstract Introduction: Endometrial cancer (EC) is the most common gynecological malignancy among women in developed countries. In the United States, it is estimated that 66,570 new cases and 12,940 deaths will occur in 2021. EC is more common in white women, but black women have a worse prognosis with higher mortality rates. Molecular characteristics in tumor tissue have been reported for potential clinical utility. Integrated genomic characterization efforts have shown common molecular alterations occurring in oncogenic pathways from bulk molecular profiling of EC tumors. However, little is known about the tumor heterogeneity in endometrial cancer. Thus, using high resolution single cell technologies, we assessed tumor heterogeneity in endometrial cancers. Our preliminary study includes endometrial tumors from five (3 African Americans, 1 Hispanic/Latino, 1 Caucasian) cases. We utilize bulk whole exome sequencing and single cell whole genome sequencing copy number variation to study tumor heterogeneity. Frozen tumor sections were used to collect and sequence single nuclei utilizing the 10x ChromiumTM single cell copy number variation (scCNV). Illumina NovasEQ600 was used to sequence the single cell libraries. Results: 1,546 cells were sequenced across five tumors. Each tumor was visually inspected through hierarchical clustering from the scCNV data. Beyond describing the heterogeneity through chromosome or chromosome arm level gains and losses in samples that included single and mixed histology tumors, we assessed clonal populations suggesting apparently different clonal evolution within samples. Mutations in cancer related genes such as TP53, PTEN and PIK3CA among others suggested a clonal tumor cell stratification. The single cell whole genome data was compared to bulk exome sequencing data to determine the power of scCNV to detect clonal populations of tumor cells. Conclusions: Using varied histologies in five EC tumors, we performed DNA-CNV analysis using single cell sequencing. This level of resolution enhanced our analysis to provide clear evidence of heterogeneity in all tumors that were assessed in our study. We plan to further expand our sample size to study the degree of heterogeneity in endometrial cancer. Citation Format: Enrique Velazquez Villarreal, Lee D. Gibbs, Dana Mahinbakht, Diane M. Da Silva, Lynda D. Roman, David W. Craig, John D. Carpten. Single cell whole genome sequencing to assess tumor heterogeneity in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 772.
Abstract 5635: Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in <i>KRAS</i>-mutant cancer
Authors: Kosuke Tanaka, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, Susumu Kobayashi
Journal: Cancer Research (2022)

Abstract Although mitochondrial DNA (mtDNA) can stimulate innate immune response that potentiates the efficacy of cancer immunotherapy, how to maximize this innate immune system in certain cancer subtypes remains unknown. Here we show that mtDNA is enriched in KRAS-mutant tumor where the dsDNA-sensor machinery cGAS-STING signaling is autonomously activated at the baseline. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate cGAS-STING pathway, that is counteracted by PRKN-mediated mitophagy to eliminate mtDNA within damaged mitochondria in KRAS-mutant tumor. Combined MEK and mitophagy inhibitors synergistically boost type I IFNs through mitochondrial stress and promote lymphocyte infiltration into the TME in a mtDNA efflux-dependent manner. Moreover, this combination enhances the efficacy of PD-1 blockade in KRAS-mutant tumor. PRKN clinically associates with KRAS/LKB1-mutant subtype, lower antigen-presenting signature, and ICB resistance. Together, targeting mtDNA renders promising strategy to enable cancer immunotherapy in KRAS-mutant cancers. Citation Format: Kosuke Tanaka, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, Susumu Kobayashi. Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5635.
Abstract 624: Classifying cGAS-STING activity links chromosomal instability with immunotherapy response in metastatic bladder cancer
Authors: Mateo Sokac
Journal: Cancer Research (2022)

Abstract The cGAS-STING pathway serves a critical role in anti-cancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T-cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by the cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance, but to date no robust method has been developed. Here, we used combined expression data from 2307 tumors from five cancer types from The Cancer Genome Atlas (TCGA) to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy treated cohort, patients without cGAS-STING activation showed very limited response to treatment, while patients with strong cGAS-STING activation showed improved response and improved prognosis, particularly among patients with high CIN and high numbers of neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this supports a role of cGAS-STING activity as a predictive biomarker in combination with measures of CIN and neoantigens for the application of immunotherapy. Citation Format: Mateo Sokac. Classifying cGAS-STING activity links chromosomal instability with immunotherapy response in metastatic bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 624.
Abstract LB082: Genome-wide CRISPR activation screen identifies PRRX2 as an enzalutamide resistance gene in prostate cancer
Authors: Yara R. Rodriguez, Kenji Unno, Mihai Truica, Zachary R. Chalmers, Young A Yoo, Rajita Vatapalli, Vinay Sagar, Jindan Yu, Barbara Lysy, Huiying Han, Sarki A. Abdulkadir
Journal: Cancer Research (2022)

Abstract Androgen receptor pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance is common. Here, we used a CRISPR activation screen to identify genes that promote enzalutamide resistance in the metastatic castration-sensitive prostate cancer cell line LNCaP. We found that activation of the TGF-β target gene, PRRX2, promoted enzalutamide resistance. PRRX2 expression is highest in double negative prostate cancer (DNPC) patients and a PRRX2-related gene signature identified a subset of DNPC patients with lower overall survival. PRRX2 expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing enzalutamide-resistant tumors to enzalutamide. High PRRX2 expression/signature in prostate cancer merit investigation as markers of enzalutamide resistance that could be reversed with CDK4/6 and BCL2 inhibitors. Citation Format: Yara R. Rodriguez, Kenji Unno, Mihai Truica, Zachary R. Chalmers, Young A Yoo, Rajita Vatapalli, Vinay Sagar, Jindan Yu, Barbara Lysy, Huiying Han, Sarki A. Abdulkadir. Genome-wide CRISPR activation screen identifies PRRX2 as an enzalutamide resistance gene in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB082.
Abstract 2554: Impact of the aged bone marrow on the anti-tumor response to melanoma
Authors: Alexis Erasta Carey, Yash Chhabra, Mitchell Fane, Laura Hueser, Gloria Marino, Daniel Zabransky, Ashani Weeraratna
Journal: Cancer Research (2022)

Abstract Melanoma is responsible for the most skin cancer-related deaths in the United States. Melanoma occurrence and severity increase with age while the anti-tumor responses decrease. There have been robust responses to immunotherapy treatments, however, there remains a subset of patients who do not benefit from these modalities. Understanding more about immune cell development and age-related changes in the bone marrow can improve patient outcomes. Our hypothesis suggests that during aging, changes in Wnt signaling reshape the aged bone marrow niche, driving precursor cells to become suppressive. This ultimately decreases the anti-tumor response to melanoma due to the skewing of hematopoiesis to yield decreased immune function. In a young and aged setting, we assess the effect of a Wnt inhibitor, sFRP1, on the development of immune cell subtypes by using flow cytometry. We have preliminarily observed in situ that sFRP1 is increased in the aged bone marrow through immunohistochemical staining. We also saw a decrease in CD4 and CD8 T-cells and an increase in CD11b positive myeloid cells in the tumors of young mice treated with recombinant sFRP1 compared to age-matched mice treated with PBS by using immunohistochemical staining. We hypothesize that the increase in sFRP1 in the bone marrow niche will impact immune cell development in the niche and the immune response at the tumor site. As a future direction, we plan to investigate combination treatments of anti-sFRP1 with immunotherapies, such as anti-PD-1. These insights could lead to improve outcomes for elderly patients with melanoma. Citation Format: Alexis Erasta Carey, Yash Chhabra, Mitchell Fane, Laura Hueser, Gloria Marino, Daniel Zabransky, Ashani Weeraratna. Impact of the aged bone marrow on the anti-tumor response to melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2554.
Abstract 455: Automating integration of histomorphologic and immunohistochemistry data using computer vision tools
Authors: Michael K. Lee, Kevin Faust, Madhumitha Rabindranath, Phedias Diamandis
Journal: Cancer Research (2022)

Abstract Background: Modern diagnostic pathology workflows involve the integration of histomorphologic, immunohistochemical (IHC), and molecular data to reach a final diagnosis. Recently, advances in deep learning have revolutionized pathology by providing the prospect for expert-level autonomous image analysis tools. Despite recent innovations in deep learning, integrating histomorphologic and molecular information found on respective H&amp;E- and IHC-stained tissue sections still remains a challenge. Here, we aim to address this issue by incorporating computer vision tools, including deep learning and scale-invariant feature transform (SIFT), to align H&amp;E-stained sections with accompanying IHC studies for automated subclassification of gliomas. Methods: To test the workflow, we trained the publicly available VGG19 convolutional neural network (CNN) using patches of pathologist-annotated H&amp;E-stained WSIs to recognize histological patterns of 16 common tissue and brain tumor classes, including diffuse glioma, meningioma, metastatic carcinoma, and schwannoma. To complement the histomorphologic analysis, we optimized several deep learning classifiers, including Mask R-CNN, to recognize various IHC markers, such as Ki-67, IDH1-R132H and ATRX, relevant for molecular subclassification of gliomas. For the integrated analysis, we employed SIFT to align lesional regions of H&amp;E and IHC images. Results: The histomorphologic classifier excelled at classification with accuracies of 100% for glioma, meningioma and metastatic carcinoma, and 93% for schwannoma (n = 125). The Mask R-CNN was tested on 147 images generated from 34 brain tumor Ki-67 WSIs and showed a high concordance with aggregate pathologists’ estimates (n = 3 assessors; y = 0.9712x -1.945, r = 0.9750). Using the deep learning classifiers and SIFT, we were able to identify tumor regions from the H&amp;E images and align them to their corresponding IHC images. This resulted in significant improvement of ATRX and IDH1-R132H quantification compared to unaligned WSIs. Finally, SIFT and partially sampling the lesional regions decreased computational time significantly without compromising accuracy. Conclusion: SIFT can work in concert with deep learning tools to help examine the histomorphologic and molecular patterns of various brain tumors and provide a framework for integrating deep learning tools to provide automated diagnoses. Citation Format: Michael K. Lee, Kevin Faust, Madhumitha Rabindranath, Phedias Diamandis. Automating integration of histomorphologic and immunohistochemistry data using computer vision tools [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 455.